The Copenhagen Actinic Keratosis Study (COAKS). A decentralised clinical trial to evaluate tolerability, safety and efficacy of daily field-directed topical treatment with cytosolic phospholipase A2 inhibitor, AVX001, in participants with actinic keratosis: protocol for a randomised controlled phase I/IIa trial.

INTRODUCTION: Actinic keratosis (AK) is the most common precancerous skin condition caused by long-term UV exposure. Given the high recurrence rate of 15%-53%, identifying safe and effective treatment options is warranted. AVX001, a cytosolic phospholipase A2α (cPLA2α) enzyme inhibitor, is a novel anti-inflammatory drug for field-directed, self-administered, topical therapy of AK. METHODS AND ANALYSIS: This study is a single-centre, randomised, vehicle-controlled, double-blind, parallel-group hybrid clinical trial in adults with multiple AK lesions Olsen grade 1 or 2. The hybrid design combines decentralised participant tasks and assessments with conventional in-clinic visits. Recruitment using targeted advertising on social media and eligibility prescreening are conducted via the Studies&Me online recruitment platform. Participants (n=60) are randomly assigned to 1 of 3 treatment arms: AVX001 gel 1%, AVX001 gel 3% or vehicle gel. The trial consists of a 4-week treatment period with daily field-directed topical application of the gel and an 8-week follow-up period. Participants attend in-clinic visits at baseline, week 4 and week 12. The remote participant trial tasks include questionnaires and upload of smartphone-obtained photos of the treated skin area using a study-specific web-based app. Both remote and in-clinic assessments of safety and efficacy will be performed. The primary objective is to evaluate the local tolerability of daily application of AVX001 gel (1% or 3%) compared with vehicle gel. Secondary objectives include safety, efficacy, dose-response efficacy relationship, treatment satisfaction and cosmetic outcome. Exploratory objectives include evaluations of tolerability and efficacy assessed by dermatologists using smartphone photos uploaded by participants, comparisons of in-clinic and remote assessments and assessment of AK-related skin changes by non-invasive optical imaging. ETHICS AND DISSEMINATION: Approved by the Ethics Committee of the Capital Region of Denmark (H-21018064) and the Danish Medicines Agency (2021032485). Results will be submitted for publication in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBERS: 2021-000934-32; NCT05164393.

ß-Lactoglobulin Is Insulinotropic Compared with Casein and Whey Protein Ingestion during Catabolic Conditions in Men in a Double-Blinded Randomized Crossover Trial.

BACKGROUND: Muscle loss during acute infectious disease is mainly triggered by inflammation, immobilization, and malnutrition. OBJECTIVE: The objective was to compare muscle protein kinetics and metabolism following ingestion of the dairy protein supplements ß-lactoglobulin (BLG), casein (CAS), and whey (WHE) during controlled catabolic conditions. METHODS: We used a randomized crossover design (registered at clinicaltrials.gov as NCT03319550) to investigate 9 healthy male participants [age: 20-40 y; BMI (in kg/m2) 20-30] who were randomly assigned servings of BLG, CAS, or WHE (0.6 g protein/kg, one-third as bolus and two-thirds as sip every 20 min) on 3 separate occasions separated by ∼6-8 wk. The participants received an infusion of lipopolysaccharide (1 ng/kg) combined with 36 h of fasting and bed rest before each study day, mimicking a clinical catabolic condition. The forearm model and isotopic tracer techniques were used to quantify muscle protein kinetics. Muscle biopsy specimens were obtained and intramyocellular signaling investigated using Western blot. RESULTS: BLG, CAS, and WHE improved the net balance of phenylalanine (NBphe) from baseline with ∼75% (P < 0.001) with no difference between interventions (primary outcome, P < 0.05). No difference in rates of appearance and disappearance of phenylalanine or in intramyocellular signaling activation was found between interventions (secondary outcomes). The incremental AUC for serum insulin was 62% higher following BLG compared with CAS (P < 0.001) and 30% higher compared with WHE (P = 0.002), as well as 25% higher in WHE compared with CAS (P = 0.006). Following BLG consumption, plasma concentrations of glucose-dependent insulinotropic peptide (GIP) increased 70% compared with CAS (P = 0.001) and increased 34% compared with WHE (P = 0.06). No significant difference was found between WHE and CAS (P = 0.12). CONCLUSION: BLG, WHE, and CAS have similar effects on muscle in young male participants during catabolic conditions. BLG showed specific, possibly GIP-dependent, insulinotropic properties, which may have future clinical implications.

Consumption of nutrients and insulin resistance suppress markers of bone turnover in subjects with abdominal obesity.

OBJECTIVE: Abdominal obesity and type 2 diabetes are associated with insulin resistance and low bone turnover along with an increased fracture risk. The mode of action is poorly understood. The bone resorption marker, C-terminal telopeptide type 1 collagen (CTX), and to a lesser extent, the bone formation marker, Procollagen type 1 N-terminal propeptide (P1NP) appear to be inhibited by food consumption. The link between food consumption, insulin resistance and bone turnover remains to be clarified. Primarily we aimed to compare the postprandial CTX, P1NP and PTH responses by two frequently applied methods in assessing metabolic health; oral glucose tolerance test (OGTT) and mixed meal tolerance test. Secondly, we explored the effect of insulin resistance on bone marker responses. METHODS: We enrolled 64 subjects with abdominal obesity. Following 10 h of fasting, subjects initially underwent a standard OGTT (300 kcal) and approximately one week later a mixed meal tolerance test (1130 kcal). Circulating CTX, P1NP and PTH were assessed on both days at time = 0, after 30 min and after 90 min for comparison of the two interventions. We analyzed glucose and insulin levels for the assessment of insulin resistance. Additionally, we measured plasma calcium levels along with the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 2 (GLP-2) in an attempt to identify possible mediators of the postprandial bone response. RESULTS: CTX, P1NP and PTH were suppressed by OGTT and the mixed meal; the latter induced a more pronounced suppression after 90 min. Calcium levels were similar between OGTT and meal. GIP and GLP-2 levels increased after both interventions, although only the meal induced a sustained increase after 90 min. Fasting P1NP was inversely associated with insulin resistance. The meal-induced suppression of P1NP (but not CTX or PTH) was inversely associated with level of insulin resistance. CONCLUSION: The acute postprandial suppression of bone turnover markers is extended after ingestion of a mixed meal compared to an OGTT. The response appears to be independent of gender and prompted by a reduction in PTH. The study additionally indicates a possible link between the development of insulin resistance and low bone turnover - which may be of key essence in the development of the fragile bone structure and increased fracture risk demonstrated in subjects with abdominal obesity and T2D.

The Combination of Whey Protein and Dietary Fiber Does Not Alter Low-Grade Inflammation or Adipose Tissue Gene Expression in Adults with Abdominal Obesity.

BACKGROUND: Abdominal obesity is characterized by low-grade inflammation and plays a central role in the development of type 2 diabetes and cardiovascular diseases. Dietary factors can influence low-grade inflammation and affect adipose tissue function. AIM: To investigate the separate and combined effects of whey protein and cereal fiber on inflammatory markers and adipose tissue gene expression in abdominal obesity. METHODS: We performed a 12-week, double-blind, randomized controlled dietary intervention in 65 adults with abdominal obesity. The participants were randomized to 4 groups using a 2 × 2 factorial design; they received either 60 g/day of whey protein or maltodextrin in combination with high-fiber wheat bran products (30 g fiber/day) or low-fiber refined wheat products (10 g fiber/day). Plasma concentrations of tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1), interleukin 1 receptor antagonist (IL-1Ra), and adiponectin were measured before and after intervention. Changes in gene expression related to inflammation, insulin signaling, and lipid metabolism were measured in abdominal subcutaneous adipose tissue. RESULTS: After intervention, TNF-α was reduced for both high-fiber groups compared with baseline, but did not significantly differ from the low-fiber groups. There were no differences in fasting or postprandial inflammatory markers between the groups. The relative gene expression of ribosomal protein S6 kinase B1 (S6K1) was increased after whey protein compared with maltodextrin consumption. CONCLUSION: Intake of whey protein in combination with high cereal fiber content did not differentially affect low-grade inflammation or adipose tissue gene expression compared with maltodextrin and low fiber content in individuals with abdominal obesity.

Acute effects of light and dark roasted coffee on glucose tolerance: a randomized, controlled crossover trial in healthy volunteers.

PURPOSE: Epidemiological evidence suggests that coffee consumption is associated with a lower risk of type 2 diabetes. Coffee contains caffeine and several other components that may modulate glucose regulation. The chlorogenic acids (CGA) in coffee have been indicated as constituents that may help to normalize the acute glucose response after a carbohydrate challenge. The aim of this study was to investigate whether two coffee beverages that differ in CGA content due to different roasting degrees will differentially affect glucose regulation. METHODS: In a controlled crossover trial, 11 healthy fasted volunteers consumed 300 mL of either light (LIR) or dark (DAR) roasted coffee, or water, followed 30 min later by a 75-g oral glucose tolerance test (OGTT). Blood samples were drawn at baseline, 30, 60, and 120 min. Differences in glucose and insulin responses and insulin sensitivity index (ISI) were analyzed. The CGA and caffeine contents in the coffees were analyzed using UPLC-MS/MS. RESULTS: No differences in glucose area under the curve (AUC) were found between treatments. Glucose concentrations were higher at 60 min after ingestion of DAR compared with water, while ingestion of LIR showed similar glucose concentrations as ingestion of water. Insulin AUC was higher after ingestion of DAR compared with water, and both coffees raised insulin concentrations and reduced ISI compared with water, with no difference between the two coffees. CONCLUSION: Two coffees with different CGA contents did not differentially affect glucose or insulin responses during an OGTT, but both increased the insulin response compared with water.